Aurora isoform selectivity: Design and synthesis of imidazo[4,5- B ]pyridine derivatives as highly selective inhibitors of aurora-A kinase in cells

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Abstract

Aurora-A differs from Aurora-B/C at three positions in the ATP-binding pocket (L215, T217, and R220). Exploiting these differences, crystal structures of ligand-Aurora protein interactions formed the basis of a design principle for imidazo[4,5-b]pyridine-derived Aurora-A-selective inhibitors. Guided by a computational modeling approach, appropriate C7-imidazo[4,5-b]pyridine derivatization led to the discovery of highly selective inhibitors, such as compound 28c, of Aurora-A over Aurora-B. In HCT116 human colon carcinoma cells, 28c and 40f inhibited the Aurora-A L215R and R220K mutants with IC50 values similar to those seen for the Aurora-A wild type. However, the Aurora-A T217E mutant was significantly less sensitive to inhibition by 28c and 40f compared to the Aurora-A wild type, suggesting that the T217 residue plays a critical role in governing the observed isoform selectivity for Aurora-A inhibition. These compounds are useful small-molecule chemical tools to further explore the function of Aurora-A in cells. © 2013 American Chemical Society.

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Bavetsias, V., Faisal, A., Crumpler, S., Brown, N., Kosmopoulou, M., Joshi, A., … Blagg, J. (2013). Aurora isoform selectivity: Design and synthesis of imidazo[4,5- B ]pyridine derivatives as highly selective inhibitors of aurora-A kinase in cells. Journal of Medicinal Chemistry, 56(22), 9122–9135. https://doi.org/10.1021/jm401115g

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